Showrunner Al Jean told THR that the series... will use a motion capture technology in which Homer's voice and motions will be depicted in an animated scene talking about things he "could only be saying live on that day."

Apparently the segment will look just like the rest of the episode, which means they'll probably be using a 3D model, but toonshading it to flatten the look, which is what we did on Faster than Night andThe Augmentalist:

Sports aside, not much these days can get audiences to tune in live, so it's a good stunt for Fox. Of course, the biggest creative conundrum for real-time animation is getting the audience to believe it is in fact actually live:

The installment will feature Homer — voiced by Dan Castellaneta — discussing topical subjects and responding to fan questions for the final three minutes of its regularly scheduled episode."...

As far as I know, this is the first time that's been done by any animated show," Jean said, noting the live bit works with the theme of the episode, which explores improv comedy. "And Dan is a great improviser."

Which only leaves the question of how to convince the 99.999% of the audience whose questions won't get answered that the ones Homer is responding to are not themselves plants. Especially since the questions have to be submitted eleven days in advance:

Fox is urging fans to tweet their questions using the hashtag #HomerLive beginning Sunday, May 1, through Wednesday, May 4.